A New Function of the S100-A4 Protein (Mts1): Mts1 Stimulates the Activation of Cytotoxic Lymphocytes via the TREM-1 Receptor.

The search for new regulators of the immune response is an important task of modern immunology. In this work, we have found that Mts1 binds with high specificity to the innate immunity receptor TREM-1 and forms a stable complex with it. The same complex was found on the cell surface of macrophages. The appearance of soluble sTREM-1 in a conditioned medium after Mts1 interaction is considered the starting point of receptor activation. PCR analysis indicates activation of proinflammatory genes IL6, IL1β, and TNF after Mts1 administration. Based on these results, Mts1 can be considered a novel TREM-1 ligand. Using limited trypsinolisis, we have identified the epitopes of Mts1 responsible for TREM-1 activation. Similar to the full-length protein Mts1, the 17aa М7 peptide (41ELPSFLGKRTDEAAFQK57) of the Mts1 protein activates the TREM-1 receptor. Incubation of human lymphocytes with the Mts1 protein of its M7 peptide results in the appearance of cytotoxic subpopulations of NK cells and T lymphocytes, able to lyse HLA-deficient cancer cells via apoptosis or necroptosis. Activated lymphocytes induce apoptosis and necroptosis in HLA-negative tumor cells. The new regulatory peptide may be potentially used for the regulation of inflammatory processes and activation of antitumor immunity.